When compared with Western countries, the morbidity of stomach cancer is high in Asian countries such as Japan and China. As a result of diffusion of medical check-ups, the widespread use of digestive endoscopes, and the development of inspection techniques, it has become possible to detect stomach cancer at an early stage, and thus the number of patients suffering from this cancer has been decreasing. Nevertheless, stomach cancer is still the second cause of death due to malignant neoplasm in the Japanese population. Thus, stomach cancer is still a main cause of death. Among several types of stomach cancers, diffuse (scirrhous) stomach cancer occurs in young people when compared with another type of stomach cancer (adenocarcinoma). Such diffuse (scirrhous) stomach cancer tends to make rapid progress, and distant metastasis or peritoneal metastasis frequently occurs, thereby resulting in poor prognosis. In many cases of scirrhous stomach cancer, it has already become impossible to carry out surgical excision at the time of diagnosis. Even if it is still possible to excise the tumor, the cancer often recurs after the treatment. Accordingly, it is highly desired to establish a novel treatment method.
The death toll from pancreatic cancer tends to increase in Japan. 21,148 people died due to pancreatic cancer in 2003. At present, such pancreatic cancer makes up 6.8% of the cancers that cause death in Japan. That is, pancreatic cancer ranks fifth cause of death after lung cancer, stomach cancer, colon cancer, and liver cancer. The world demographic data was analyzed, and the age-adjusted mortality rate, which is used for comparison among the mortality rates of populations with different age structures, was calculated. As a result, in 2000, in the case of 100,000 males, 8.6 people died due to pancreatic cancer in Japan, whereas 7.3 people died in the United States and 6.3 to 7.0 people died in the United Kingdom due to the same type of cancer. In the case of 100,000 females, 4.9 people died due to pancreatic cancer in Japan, whereas 5.3 people died in the United States and 4.8 to 5.1 people died in the United Kingdom due to the same type of cancer. Thus, the mortality rate due to pancreatic cancer in Japan has become the same level as those of Western countries.
Taking into consideration the age-adjusted rate in 2000 (100,000 people of the world's population), in the case of males, 8.6 people died due to pancreatic cancer in Japan, whereas 7.3 people died in the United States and 6.3 to 7.0 people died in the United Kingdom due to the same type of cancer. In addition, in the case of females, 4.9 people died due to pancreatic cancer in Japan, whereas 5.3 people died in the United States and 4.8 to 5.1 people died in the United Kingdom due to the same type of cancer. Thus, the mortality rate due to pancreatic cancer in Japan has become the same level as those of Western countries. In spite of the development of diagnostic imaging, at present, approximately 40% of the total Japanese patients with pancreatic cancer suffer from progressive pancreatic cancer involving distant metastasis, and further, there are also many cases where the cancer is discovered after it has reached a locally-advanced cancer stage, at which tumor cannot be excised. The 5-year relative survival rate of total patients with pancreatic cancer is 4.3% in the diagnosis cases in 1996. Although this rate tends to be higher than the conventional survival rate (2% to 3%), it is still low. Regarding factors of developing pancreatic cancer, it has been suggested that various factors including life habit such as smoking, adiposis, meals, alcohol drinking, and coffee use, as well as chronic pancreatitis, diabetes, genetic factor, etc. are involved in the onset of pancreatic cancer.
Pancreatic cancer does not have specific symptoms, and thus, in many cases, the cancer has already progressed when certain symptoms appear. As a result, the 5-year survival rate of total patients is 5% or less, and prognosis after the diagnosis is extremely low. Due to difficulty in the diagnosis of pancreatic cancer, the rate of this cancer as a causative disease of cancer death is gradually increased particularly in advanced countries. Currently, multidisciplinary therapy including a surgical excision as a main treatment, a radiotherapy, and a chemotherapy, has been carried out. However, no drastic improvement of therapeutic effects can be obtained, and thus, the establishment of a novel therapeutic strategy is urgently necessary.
Melanoma is one type of skin cancer, which is often called malignant melanoma. Among several types of skin cancers, melanoma is highly likely to become infiltrative and metastatic and has the highest grade of malignancy, and thus it is greatly feared. Among cells that constitute skin, several cells generate melanin pigment. Such cells are called melanocytes. When such melanocytes become cancerous, melanoma occurs. In addition, the frequency of occurrence of melanoma has been increasing, particularly among Caucasians, as a result of an increase in exposure to ultraviolet rays due to a reduction in the ozone layer in the atmosphere caused by environmental destruction.
In Japan, the incidence of melanoma varies from 1.5 to 2 people in 100,000 in the general population. Thus, it is estimated that approximately 1,500 to 2,000 people develop melanoma per year. On the other hand, in the Western countries, more than a dozen of people develop melanoma in 100,000 in the general population. In particular, in Australia, twenty or more people develop such melanoma in 100,000 in the general population, and thus it is known that the incidence of melanoma in Australia is the highest in the world. Under such circumstances, people who live in Europe, the United States, and Australia are interested in melanoma, and they pay attention to the occurrence of melanoma. Furthermore, surprisingly, the occurrence of melanoma tends to be increasing year after year in Japan as well as in foreign countries. According to recent studies, the annual death toll from melanoma is approximately 450 in Japan. Melanoma develops regardless of age. However, the incidence of this disease increases for those over 40, and it is the highest for those in their 60's and 70's. The onset of this disease in childhood is extremely rare, but this does not mean that the disease never develops in childhood. Recently, the occurrence of melanoma tends to be increasing in young patients in their 20's and 30's. Melanoma develops regardless of sex, and both male and female patients suffer from this disease. In the case of Japanese patients, the site at which melanoma is most likely to develop is the sole (the sole of the foot), and it accounts for 30% of all instances of melanoma. As characteristics of Japanese patients, melanoma also develops in the foot and the nail portions of the fingers. In addition, as in the case of Western patients, melanoma develops in all parts of the skin, such as the body, hand, foot, face, and head.
At present, methods that can be applied to treat melanoma include a surgical therapy, a chemotherapy, and a radiotherapy. However, as a therapy for alleviating the symptoms of metastatic cancer or intractable cancer, to which the aforementioned therapy cannot be applied, an immunotherapy for enhancing the immunity of a cancer patient to cancer so as to suppress the growth of the cancer has become a focus of attention. Such an immunotherapy is actually effective for some patients.
On the other hand, with the development of molecular biology and tumor immunology in recent years, it has been revealed that cytotoxic (killer) T cells and helper T cells recognize peptides generated by degradation of proteins highly and specifically expressed in cancer cells, which are presented on the surfaces of the cancer cells or antigen-presenting cells via HLA molecules, and that they exhibit an immune reaction for destroying such cancer cells. Moreover, a large number of tumor antigenic proteins and peptides derived from them, which stimulate such an immune reaction for attacking cancers, have been identified, and clinical application of an antigen-specific tumor immunotherapy has been advanced.
HLA class I molecules are expressed on the surfaces of all nucleated cells in a body. Proteins generated in cytoplasms and nuclei provide peptides generated as a result of being degraded in cells, and they are expressed on the surfaces of such cells. On the surfaces of normal cells, peptides derived from normal autologous proteins bind to HLA class I molecules, and T cells of the immune system neither recognize nor destroy such peptides bound to HLA class I molecules. On the other hand, in a process in which cancer cells are converted to a cancer, such cancer cells may express large amounts of proteins, which are hardly expressed or are only expressed in small amounts on normal cells. If a peptide generated by degradation in the cytoplasm of such a protein that is highly expressed specifically in a cancer cell binds to an HLA class I molecule and is expressed on the surface of such a cancer cell, a killer T cell recognizes the peptide and destroys only the cancer cell. In addition, by immunizing such a cancer-specific antigen or peptide to an individual body, it is possible to destroy cancer cells and suppress the growth of a cancer, without impairing normal cells. This is referred to as cancer immunotherapy using a cancer-specific antigen. Moreover, an HLA class II molecule is mainly expressed on the surface of an antigen-presenting cell. Such an HLA class II molecule binds peptides derived from a cancer-specific antigen generated by incorporating the cancer-specific antigen from outside the cell and degrating it in the cell, and it is expressed on the surface of the cell. A helper T cell, which has recognized the peptides bound to HLA class II molecule, is activated to generate various cytokines that activate other immunocompetent cells, so as to induce or reinforce an immune reaction against a tumor.
Thus, if an immunotherapy targeting an antigen specifically expressing at a high level in such a cancer can be developed, it can provide a therapeutic method effectively eliminating the cancer alone, without impairing normal autologous organs. Moreover, it is anticipated that such an immunotherapy can provide a therapeutic method applicable to patients suffering from a terminal-stage cancer, for whom no other treatments can be implemented. Furthermore, if a cancer-specific antigen and peptide are administered in the form of a vaccine to a human having a high risk of developing such a cancer, there is a possibility that the onset of the cancer can be prevented.
First, the present inventors have performed a genome-wide gene expression analysis. They have analyzed 23,040 types of genes in stomach cancer tissues and normal tissues utilizing a cDNA microarray. As a result, in 11 out of 20 cases of patients with diffuse infiltrative stomach cancer, the inventors have identified Secreted protein acidic and rich in cysteine (SPARC), which is a gene highly expressed in stomach cancer tissues, and the expression level of which is 5 or more times higher than that of normal tissues (130,000 times higher on average) (FIG. 1). The SPARC gene is expressed at a low level also in normal adipose tissues, mammary gland, ovary, spinal cord, testis, uterus, placenta, etc. However, the expression level of the SPARC gene in any of the aforementioned organs is lower than that of normal gastric mucous membrane by a factor of 5 times or less (FIG. 2).
Other researchers had already reported that SPARC is not only highly expressed in diffuse infiltrative stomach cancer but it is also expressed in pancreatic cancer and melanoma. Moreover, the present inventors have found that SPARC is secreted in the serum of melanoma patients, and that SPARC can be a useful tumor marker particularly for the early detection of melanoma (Japanese Patent Application No. 2004-303688; and Clinical Cancer Research 11: 8079-8088, 2005).
SPARC is a 43-KD acidic secretory protein consisting of 286 amino acids. This protein is rich in cysteine, and it moves to the nucleus during the cell division phase. In addition, SPARC controls the interaction between an extracellular matrix protein and a cell, so that it can be also associated with the control of cell growth. Since SPARC is expressed in osteoblasts, thrombocytes, and wound areas, it is considered that this protein is associated with the repair and reconstruction of tissues. Furthermore, it has also reported that SPARC is highly expressed also in cancers such as melanoma or osteosarcoma and in the interstitial cells of tumors, and that the expression of SPARC correlates with the prognosis, infiltration or metastasis of tumors.    [Non-Patent Document 1] Ikuta Y et al., Clinical Cancer Research 11: 8079-8088, 2005.    [Patent Document 1] Japanese Patent Application No. 2004-303688